The brain exerts a powerful influence on the spinal transmission of pain signals. Recent evidence from our laboratory suggests that the locus coeruleus (LC), an important brainstem noradrenergic center, facilitates the mechanical and thermal hypersensitivity induced by injury to peripheral nerves. These findings led to the hypothesis that in the setting of peripheral nerve injury, descending facilitatory influences from the LC are required for the expression of nerve injury-induced pain (Aim #1), in part by increasing nociceptive processing at the dorsal horn (Aim #2). AIM #1a will test the hypothesis that disruption of synaptic activity in the LC with the microinjection of either a local anesthetic (lidocaine) or a synaptic inhibitor (cobalt) will decrease the tactile and cold hypersensitivity that develops following transection of the tibial and common peroneal branches of the sciatic nerve, leaving the sural nerve intact. Aim #1b will test the hypothesis that irreversible destruction of LC neurons with a noradrenergic neurotoxin (DSP-4) before sham or nerve injury will prevent or reduce the development of injury-induced hypersensitivity. Aim #2 will use similar strategies in combination with measurement of stimulus-evoked expression of c-fos in the dorsal horn to test the hypotheses that disruption of LC function will: (a) prevent or (b) reverse nerve injury-induced spinal nociceptive processing. This two-year R21 study seeks to firmly establish whether the LC exerts facilitatory influences that contribute to the expression of neuropathic pain. The results achieved will provide the basis for an R01 application to further investigate the supraspinal network mediating descending facilitation. Increased understanding of the supraspinal noradrenergic mechanisms underlying chronic neuropathic pain may help to identify entirely new classes of analgesic drugs that may work by directly or indirectly blocking descending facilitation.